Varicella zoster virus (VZV) causes chickenpox and shingles. Virus infection of cells is known to trigger several signaling pathways that are important for cell proliferation and prevention of programmed cell death (also known as apoptosis). We have used a virus genome wide approach to identify functions of VZV proteins. Nearly all VZV genes were individually expressed in tissue culture cells along with a reporter system that responds to specific signaling proteins. Screening the VZV genome, we found that VZV ORF12 protein activated two protein kinases (ERK1/2 and p38). VZV deleted for ORF12 was impaired for activation of the kinases. ORF12 protein was shown to be located in the virus tegument (between the virus envelope and the nucleocapsid). We also found that ORF12 inhibits programmed cell death (apoptosis) induced by chemical treatment of the cells. These experiments indicate that ORF12 protein can activate signaling pathways and inhibit programmed cell death.